This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Small molecule metabolism is a tempting yet treacherous domain for drug discovery. Numerous drugs target metabolic enzymes in humans and bacteria, often mimicking their substrates, with both therapeutic and toxic effect. To provide a large-scale overview of the intersection between drugs and metabolism, we first group drugs and metabolites by their associated targets and enzymes, then create ligand-based set signatures to quantify their degree of difference in chemical space. This 'roadmap'illustrates what chemical space surrounding metabolism has been explored, where successful drugs have been found, and what novel territory remains. Using links between drug and metabolite sets, we predict the 'effect space'comprising a drug's likely metabolic targets. These links indicate potential toxicity, suggest routes of metabolism, and reveal drug polypharmacology. To aid other researchers in their drug discovery efforts, we have created an online resource of species-specific maps linking drugs to metabolism for 385 model organisms and pathogens in the BioCyc database collection. We have applied our method to select and then experimentally confirm novel drug targets in the rising pathogenic threat methicillin-resistant Staphylococcus aureus.